When To Start Thyroid Hormone Replacement in Cats Treated with Radioiodine (I-131)

I have a question about thyroid hormone supplementation for iatrogenic hypothyroidism, especially in cats treated with radioiodine (I-131). More specifically, how long after radioactive iodine therapy do you wait before recommending supplementing hypothyroid cats with thyroxine?

I work as a small animal internist at a referral hospital where we treat hyperthyroid cats with radioiodine. After treatment, we routinely run serum T4 and free T4 concentrations and full blood work 30 and 90 days after the cat is discharged. I have found that about 20% of these cats are biochemically hypothyroid (low total or free T4 values) at the 30-day recheck, but many of these cats will revert to normal by the 90-day recheck. The other internist at my practice supplements these cats with L-thyroxine at the first recheck if the serum T4 and free T4 values are low. She does this even if they are not azotemic, with the rationale being that the studies show that hypothyroid cats develop worsening azotemia, which can affect their survival (1).

I am not sure if this is the best approach since I have heard that the residual thyroid follicles may take a few months to regain full function after being suppressed by the over-active thyroid tissue for so long. However, I just want to do what's best (don't we all!)

Thank you so much. I enjoy reading your website and attending your lectures at conferences.

My Response:

First of all, I don't find that free T4 determinations are all that helpful in the diagnosis of feline hypothyroidism (2-4). Many cats treated with radioiodine with maintain low-normal values for both total and free T4 but develop high serum TSH concentrations, a situation commonly referred to as subclinical hypothyroidism in human patients. The problem with our cats, however, is that although most of these cats do remain nonclinical for hypothyroidism, many will develop azotemia that will progressively worsen without treatment with thyroid hormone replacement.

So what I do is as follows: at 30-days post-treatment, I monitor serum concentrations of T4, free T4, and TSH, along with a serum chemistry panel to follow kidney values. If T4 or free T4 values fall into the lower third of the reference range (below 1.5-2.0 µg/dl; reference interval ≈1-4 µg/dl) and TSH rises (above 0.5-0.6 ng/dl; reference range, 0.03-0.03 ng/ml), then the cat is mildly hypothyroid. Some of these cats will recover enough thyroid function to end up as euthyroid, but most remain mildly hypothyroid at both 3 and 6 months, at least based on the finding of high TSH concentrations.

In these cats with mild or subclinical hypothyroidism, I don't like to treat with levothyroxine (LT4) at this time unless evidence of chronic kidney disease (CKD) has developed, with serum creatinine values rising from normal to greater than 2.0 mg/dl. However, this definitely indicates the need for LT4 replacement in order to help maintain renal perfusion and stabilize the serum creatinine concentrations (3-5).

If we decide not to treat (which is generally the case unless new azotemia has developed), then we monitor again with the same thyroid and renal profiles at 3- and 6 months. Again, if T4 falls into the low-normal range (less than 1.5-2.0 µg/dl) and TSH is clearly high (above 0.5-0.6 ng/dl), I would definitely supplement if new or worsening azotemia is detected. If no azotemia is present, I generally continue to monitor and don't supplement with LT4 unless azotemia does develop.

Now, if the serum T4 is below normal and the TSH is clearly high at 3 or 6 months (or later), then the cat has overt hypothyroidism (no longer subclinical) and I would definitely supplement with L-T4 (2-4). Many of these cats are still not very symptomatic, but that may simply be a matter of time. If left untreated for 1 to 2 years, most of those cats will develop classical signs of hypothyroidism (eg, lethargy, hair loss, etc).

So in your case, I would add-in serum TSH to your monitoring protocol. If your owners find that too expensive, then I would replace the free T4 measurement with TSH determination, which is more more helpful in monitoring for cats treated with radioiodine.

References:

1. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 
2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4.  
3. Peterson ME. Diagnosis and management of iatrogenic hypothyroidism In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
4. Peterson ME, Guterl JN.Subclinical iatrogenic hypothyroidism in the cat: Clinical, laboratory, and thyroid scintigraphic findings in 35 cases. J Vet Intern Med 2015;29:448-449.
5. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255.

Top Endocrine Publications of 2014: The Canine Thyroid Gland

Large goiter due to thyroid carcinoma

In my third compilation of the canine and feline endocrine publications of 2014, I’m moving on to disorders of the canine thyroid gland. Listed below are 21 research papers written in 2014 that deal with a variety of thyroid gland topics and issues of clinical importance.

A number of these publications deal with clinical, pathologic, diagnostic, or therapeutic aspects of thyroid carcinoma (1-6,10,13,14,17,18).  Of these, two papers (1,14) deal specifically with ectopic thyroid tumors arising in the sublingual location, which may indicate that such ectopic tumors are not as uncommon as once thought.

Other publications include a case report of a hypothyroid dog suffering from insulin-resistant diabetes mellitus and acromegaly (8); interestingly, after treatment with L-thyroxine, the insulin resistance and diabetes resolved.

Other papers report on various studies on hypothyroidism in dogs including the effect of age of lipid metabolism (9) to the association between gall bladder mucoceles and hyperlipidemia (12);  and from exercise-induced hypercoagulability, von Willebrand factor, and thyroid hormone concentrations in sled dogs (11) to evaluation of serum thyroid hormones in dogs with systemic inflammation or sepsis (16).

Finally, other papers include a case report of a hypothyroid dog with polyneuropathy that resolved following thyroid supplementation (20), to a study of the pharmacokinetics of total T4 after repeated oral administration of L-T4 solution in hypothyroid dogs (21). 

References:

1. Broome MR, Peterson ME, Walker JR. Clinical features and treatment outcomes of 41 dogs with sublingual ectopic thyroid neoplasia. J Vet Intern Med 2014;28:1560-1568. 
2. Campos M, Ducatelle R, Kooistra HS, et al. Immunohistochemical expression of potential therapeutic targets in canine thyroid carcinoma. J Vet Intern Med 2014;28:564-570. 
3. Campos M, Ducatelle R, Rutteman G, et al. Clinical, pathologic, and immunohistochemical prognostic factors in dogs with thyroid carcinoma. J Vet Intern Med 2014;28:1805-1813. 
4. Campos M, Kool MM, Daminet S, et al. Upregulation of the PI3K/Akt pathway in the tumorigenesis of canine thyroid carcinoma. J Vet Intern Med 2014;28:1814-1823. 
5. Ciaputa R, Nowak M, Kandefer-Gola M, et al. Morphological and immunohistological characteristics of follicular-compact thyroid carcinoma in dog. Folia Histochem Cytobiol 2014;52:157-161. 
6. Deitz K, Gilmour L, Wilke V, et al. Computed tomographic appearance of canine thyroid tumours. J Small Anim Pract 2014;55:323-329. 
7. Higgs P, Costa M, Freke A, et al. Measurement of thyroxine and cortisol in canine and feline blood samples using two immunoassay analysers. J Small Anim Pract 2014;55:153–159. 
8. Johnstone T, Terzo E, Mooney CT. Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. Aust Vet J 2014;92:437-442. 
9. Kawasumi K, Kashiwado N, Okada Y, et al. Age effects on plasma cholesterol and triglyceride profiles and metabolite concentrations in dogs. BMC Vet Res 2014;10:57. 
10. Kobayashi R, Yamada N, Kitamori T, et al. Follicular thyroid carcinoma characterized by abundant stromal components with chondroid and osseous metaplasia in a dog. J Vet Med Sci 2014;76:1161-1164. 
11. Krogh AK, Legind P, Kjelgaard-Hansen M, et al. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs. Acta Vet Scand 2014;56:11. 
12. Kutsunai M, Kanemoto H, Fukushima K, et al. The association between gall bladder mucoceles and hyperlipidaemia in dogs: A retrospective case control study. Vet J 2014;199:76-79. 
13. Metivier KS, Deitz K, Xu WW, et al. Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs. Vet Comp Oncol 2014;12:181-197. 
14. Milovancev M, Wilson DM, Monnet E, et al. Partial resection of the hyoid apparatus during surgical treatment of ectopic thyroid carcinomas in dogs: 5 cases (2011-2013). J Am Vet Med Assoc 2014;244:1319-1324. 
15. Muller TR, Assis MM, Doiche DP, et al. Do thyroid ultrasonographic features change according to age in euthyroid dogs? Anat Histol Embryol 2014;43:468-473. 
16. Pashmakova MB, Bishop MA, Steiner JM, et al. Evaluation of serum thyroid hormones in dogs with systemic inflammatory response syndrome or sepsis. J Vet Emerg Crit Care (San Antonio) 2014;24:264-271. 
17. Pessina P, Castillo V, Sartore I, et al. Semiquantitative immunohistochemical marker staining and localization in canine thyroid carcinoma and normal thyroid gland. Vet Comp Oncol 2014. 
18. Pineyro P, Vieson MD, Ramos-Vara JA, et al. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog. J Vet Sci 2014;15:449-453. 
19. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats. Vet Clin Pathol 2014;43:1-3. 
20. Utsugi S, Saito M, Shelton GD. Resolution of polyneuropathy in a hypothyroid dog following thyroid supplementation. J Am Anim Hosp Assoc 2014;50:345-349. 
21. van Dijl IC, Le Traon G, van de Meulengraaf BD, et al. Pharmacokinetics of total thyroxine after repeated oral administration of levothyroxine solution and its clinical efficacy in hypothyroid dogs. J Vet Intern Med 2014;28:1229-1234. 

Dog on Long-Term Thyroid Hormone Supplementation: Hypothyroid, Hyperthyroid, or Cushing's Syndrome?

My patient is an 11-year old, spayed female Spaniel-Mix, named Molly. She weighs 31 pounds (14.1 kg) and is slightly overweight, with a body condition score of 7/9. About 5 years ago, she was initially diagnosed as having hypothyroidism based upon clinical signs of hair loss, together with low serum concentrations of total thyroxine (T4) and free T4. Molly responded well to thyroid hormone replacement with brand-name levothyroxine (L-T4) at the dose of 0.2 mg, twice daily.

Over the following 3 years, the dog did well (complete hair regrowth), but the daily L-T4 dose was increased (to 0.3 mg, twice daily) based on post-pill serum T4 testing, done about 5 hours after administration of the morning dose.

About 2 years ago, Molly was seen for new hair loss, increased appetite, and polyuria and polydipsia (PU/PD). Results of a CBC and serum chemistry panel were considered to be normal, and a post-pill serum T4 concentration was low-normal at 1.5 µg/dl (40 nmol/L). A complete urinalysis was unremarkable, other than a urine specific gravity of 1.013. Based on Molly's relapse of her hair loss and low-normal post-pill T4, the L-T4 dose was increased to 0.4 mg, BID.

Follow-up thyroid testing 6 months later revealed a post-pill serum T4 value in the high-normal range (3.9 µg/dL; 50 nmol/L) so the L-T4 was maintained at 0.4 mg BID. At that time, the PU/PD had lessened, and the increased appetite had normalized so no further workup was recommended.

On followup 1 year later (now 5 months ago), Molly again presented with increased appetite and more severe PU/PD. Her post-pill total T4 concentration was quite high at was 10.1 µg/dl (130 nmol/L), so the dosage of LT4 was decreased to 0.2 mg, BID. Repeat testing 2 months later revealed that the serum T4 value remained high (5.5 µg/dL; 70 nmol/L) so administration of L-T4 was discontinued. Other than truncal hair thinning, Molly's physical examination at that time was normal, with a normal heart rate (85 bpm); no thyroid masses could be palpated.

Now 3 months later, the owner reports progressive truncal hair loss, PU/PD, increased appetite, panting, and weight gain. Molly's physical exam was again unremarkable. Results of routine testing revealed a normal CBC (no stress leukogram), with severe hypercholesterolemia (660 mg/dL; 17.0 mmol/L). The serum alkaline phosphatase activity was also moderately high at 311 U/L (reference interval less than 100 U/L).

We next ran a complete thyroid profile, with the following results:

• Total T4: 16 nmol/L (reference interval, 11-60 nmol)
• Total T3: 0.4 nmol/L (reference interval, 0.8-2.1 nmol)
• Free T4 by dialylsis: 12 pmol/L (reference interval, 10-50 pmol/L)
• TSH: 1.0 ng/ml (reference interval, 0-0.6 ng/ml)
• Thyroglobulin autoantibodies: 10% (reference interval, 0-35%)

I'm at a loss. I thought that the dog's signs might indicate hyperthyroidism but these results appear to be most consistent with hypothyroidism. Should L-T4 be restarted? We have only used a single brand-name L-T4 preparation in this dog — should we switch to another product?

Should I be testing Molly's pituitary-adrenal axis to rule out Cushing's syndrome?

My Response:

This dog is indeed a rather complicated case. Looking back at the history, Molly has displayed clinical signs of hair loss, PU/PD, and increased appetite for the past 2 years. All of these signs have waxed and waned in severity over this time, which explains her long duration of illness.

During that entire time, she was being treated with adequate replacement doses of thyroid hormone and never had post-pill T4 values that were low. In fact, many of her serum T4 concentrations checked during monitoring were too high— clearly in the hyperthyroid range (1). Overall, this strongly suggests that hypothyroidism alone cannot explain all the dog's problems, a conclusion that also is consistent with the fact that neither PU/PD nor increased appetite are signs of thyroid hormone deficiency (2,3).

Hypothyroid or hyperthyroid?
Given the fact that 2 of the post-pill serum T4 values were high, could this dog have iatrogenic hyperthyroidism secondary to an overdosage of L-T4? That certainly is possible, and thyrotoxicosis could account for the increased appetite and PU/PD (4-6). In fact, almost all hyperthyroid dogs will develop moderate to marked PU/PD, which is a much more prominent sign in dogs than in most cats with hyperthyroidism (7).

However, these signs persisted for 3 months after we stopped all thyroid hormone supplementation. In addition, the last thyroid hormone panel showed low to low-normal serum concentrations of total T4, T3, and free T4, in conjunction with high serum concentration of TSH; this combination of results is most consistent with primary hypothyroidism (the original diagnosis) (2,3). Overall, these findings completely rule out either natural hyperthyroidism associated with a hyperfunctional thyroid tumor or iatrogenic thyrotoxicosis from overdosage of L-T4 (5-7).

Hypothyroid or Cushing's syndrome?
Since Molly's clinical signs are also classical for hyperadrenocorticism, we should consider testing for that common canine disorder. While the high cholesterol concentration could be due to hypothyroidism or Cushing's syndrome, the finding of a high serum alkaline phosphatase activity certainly is consistent with chronic cortisol excess (8,9).

Before embarking on a workup for spontaneous Cushing's syndrome, remember to first make sure that Molly is not on any exogenous steroids, including a topical preparation for her eyes, ears, or skin, which can result in iatrogenic hyperadrenocorticism. You determine that not only by reviewing the record to see what your hospital has dispensed, but also by asking the owner what they're using to treat their dog, as they may have bags of steroid medications at home that weren't dispensed by you.

If Molly is suffering from Cushing's syndrome, it is possible that chronic cortisol excess is contributing to the low serum thyroid hormone concentrations.  Canine Cushing's syndrome can actually produce a secondary form of hypothyroidism, one that is reversible upon correction of the hyperadrenocorticism (10,11). However, it is very unlikely that Molly has had undiagnosed Cushing's disease for the past 5 years, given that she appears to be doing so well clinically. In addition, chronic cortisol excess suppresses serum TSH values (9,11), so Molly's high TSH value goes along more with primary hypothyroidism than a secondary form of hypothyroidism resulting from Cushing's syndrome.

As you continue to work up this dog, I would restart your thyroid hormone supplementation at a low dose (0.2-0.3 mg per day, divided). The dog certainly appears to be hypothyroid, based on the last serum thyroid profile, as well as worsened hair loss.

Causes of marked variation in L-T4 absorption
The marked variation in serum post-pill T4 concentrations are both interesting, as well as somewhat perplexing.

I'd start by questioning the owners about the timing of L-T4 administration, since the absorption of the medication is known to be increased when given on an empty stomach, as compared to when administered with meals (12,13). Could some of the marked variation in her past serum post-pill T4 levels have been due to administration of the drug with meals on some occasions and on an empty stomach on others? 

Other drugs and medications can also have an effect on L-T4 absorption (14). In this dog, we must carefully record all dietary changes as well as any administered drugs or supplements, all of which could potentially alter the absorption of the L-T4 preparation. 

References:

1. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
2. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
3. Mooney CT. Canine hypothyroidism: a review of aetiology and diagnosis. N Z Vet J 2011;59:105-114. 
4. Bosje T, den Hertog E, Dijksta M. Does the T4 measurement belong in the standard blood analysis in polyuria/polydipsia? Tijdschr Diergeneeskd 2013;138:230-231. 
5. Peterson ME. Hyperthyroidism and thyroid tumors in dogs In: Melian C, Perez Alenza MD, Peterson ME, et al., eds. Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Barcelona, Spain: Multimedica, 2008;113-125.
6. Mooney CT. Canine hyperthyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;86-91.
7. Nichols, R., Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Gloucester: British Small Animal Veterinary Association, 2012;215-220.
8. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;167-189.
9. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
10. Peterson ME, Ferguson DC, Kintzer PP, et al. Effects of spontaneous hyperadrenocorticism on serum thyroid hormone concentrations in the dog. Am J Vet Res 1984;45:2034-2038. 
11. Ferguson DC, Peterson ME. Serum free and total iodothyronine concentrations in dogs with hyperadrenocorticism. Am J Vet Res 1992;53:1636-1640. 
12. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876.
13. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101.
14. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.

Treatment and Monitoring of Hypothyroid Dogs with Thyroid Hormone Autoantibodies

I'm a veterinarian from Finland, and I'd like your opinion and advice on a 2-year old, male neutered Doberman Pincher (body weight, 42 kg). This dog had been diagnosed with hypothyroidism together with serum T3 antibodies by another veterinarian.

Clinically, the dog has shown a partial response to treatment with L-thyroxine (L-T4), but serum T4 concentrations remain very low and serum TSH remains high on post-pill testing. These are results of my thyroid testing (always at 4 hours post-pill), together with the L-T4 dose and physical examination:

Initial exam:

• Dose: Levothyroxine 400 µg BID
• Exam findings: Clinically quite normal but slightly overweight
• Total T4:  <9.0 nmol/L (reference interval =  13 - 52 nmol/L)
• Free T4 (CLIA): >77 pmol/L (reference interval =  8 - 48 pmol/L )
• TSH: 3.24 ng/ml (reference interval = less than 0.5 ng/ml)

4-week recheck:

• Dose: Levothyroxine 500 µg BID
• Exam findings: Clinically normal; but still overweight
• Total T4: < 9.0 nmol/L  
• TSH: 3.59 ng/ml  

8-week recheck:

• Dose: Levothyroxine 600 µg BID
• Exam findings: Mild weight loss, heart rate 82/bpm, very active and perky
• Total T4: <9.0 nmol/L  
• Free T4 (CLIA): 62 pmol/L
• TSH: 2.2 ng/ml  

I reviewed the L-T4 supplementation with the owner and made sure the dog is ingesting the pills and made certain that they administered the thyroid medication the morning of each recheck—  no problem there. I next recommended repeat testing, again looking at the autoantibody levels and free T4 measured by equilibrium dialysis (ED).

11-week recheck:

• Dose: Levothyroxine 800 µg BID
• Exam findings: Normal
• Total T4: < 9.0 nmol/L 
• Free T4 (ED): 8 pmol/L (reference interval = 6-40 pmol/L) 
• TSH: 1.5 ng/ml  
• T4 antibodies: 13% (1-20%)
• T3 antibodies: 43% (1-10%)
• Thyroglobulin autoantibodies: positive

Overall, I'm confused about this dog's thyroid status. Biochemically, this dog appears to have persistent hypothyroidism (low T4, high TSH) but may also have iatrogenic hyperthyroidism (high free T4 values). How do I know?

I also need advice about how to determine the correct L-T4 replacement dose for this dog. Do I just keep on increasing the medication until the serum T4 concentration normalizes?

My Response:

Obviously, your testing confirms that this dog has thyroiditis, with positive thyroglobulin autoantibodies and high levels of T3 autoantibodies (1-4). Based on the low serum concentrations of free T4 by dialysis and high TSH levels, the dog certainly is hypothyroid (5), but it does not appear that the dog is responding well to the L-T4 supplementation.

Method for T4 assay
What method is being used to measure total T4 concentrations? These days, most commercial veterinary labs don't use radioimmunoassay (RIA) to measure serum T4, even though that method is still considered the gold standard (5,6). Most laboratories use either a chemiluminescent immunoassay method (CLIA; Immulite) or an automated enzyme immunoassay (EIA) method (7,8).

For some reason not well understood, the EIA method will fail to accurately detect circulating post-pill T4 values, at least in some T4-treated dogs. In other words, the serum T4 values remain falsely low, even when the actual T4 values are within the mid- to high-normal range and the dogs are clinically improved. This issue needs more research and has not been published, but there is no doubt that the problem exists. If suspected, one can verify the problem very easily, simply by repeating the post-pill serum T4 concentration by either RIA or chemiluminescence.

Method for Free T4 assay
In this dog, the finding of a high free T4, measured by CLIA (Immulite) can not be easily explained. The fact that the serum TSH is persistently high in your dog suggests persistent hypothyroidism, not hyperthyroidism (5,9).  The low-normal value for the free T4 concentration, when remeasured by equilibrium dialysis (ED), also points to hypothyroidism. Thyroid autoantibodies can not interfere with the free T4 value when determined by the dialysis method, since all protein molecules (including the thyroid autoantibodies) are removed (dialyzed) prior to assay.

Given that we know your dog has thyroid hormone autoantibodies, it's tempting to postulate that the high free T4 value measured by CLIA are falsely high due to the autoantibodies. The bottom line is that we just don't know. However, what is clear is that these free T4 values are not helping us to determine the best treatment for this dog — only confusing the situation.

Brand of L-thyroxine
What brand of LT4 is being administered? In any dog that is not responding well to thyroid hormone supplementation, a brand name product is always recommended.  In addition, sometimes it can help to switch to another size or brand, suggesting that the absorption rate may vary slightly between products. In some studies, use of a liquid L-T4 solution has been found to be be better absorbed, at least in select patients (10,11).

Timing of L-T4 and meals
Are the owners giving the LT4 with meals or on an empty stomach?  The standard of care for human patients requiring L-T4 is to administer the drug on an empty stomach, generally an hour before meals.

Simultaneous administration of L-T4 with food can markedly delay and inhibit the absorption of the drug in both humans and dogs (11-13). In one study of dogs, giving the L-T4 with food decreased its absorption by about 45% (11).

Follow-up Information:

The serum T4 is being measured by EIA. We are giving a brand-name L-T4 product (14). The owner is consistently giving the L-T4 at 12-hour intervals at the time of meals. No other medication is being given.

My Response:

Again, with the EIA method, the total T4 result may not be accurate when measuring a post-pill T4 concentration. We need to do the post-pill T4 by either chemiluminescence (CLIA; Immulite) or RIA on the next followup.

However, the fact that the free T4 concentration is low-normal and the TSH is still high means that the absorbed dose of L-T4 is not high enough. None of your problems appear to have anything to do with T4 or T3 autoantibodies.

I'd first change the timing between the L-T4 dose and feeding to ensure "empty stomach dosing." If that fails to adequately increase the total T4 concentration (RIA or CLIA) and normalize the high serum TSH concentrations, I'd next consider switching to a liquid L-T4 preparation to see if that helps. Finally, if all else fails, you may have to continue to increase the L-T4 dose, but at 0.8 mg twice daily, your dog is already on a more-than-adequate dose for most dogs (5).

References:

1. Refsal KR, Nachreiner RF. Thyroid hormone autoantibodies in the dog: their association with serum concentrations of iodothyronines and thyrotropin and distribution by age, sex, and breed of dog. Canine Practice 1997;22:16-17.
2. Young DW. Antibodies to thyroid hormone and thyroglobulin in canine autoimmune lymphocytic thyroiditis. Canine Practice 1997;22:14-15. 
3. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc 2002;220:466-471. 
4. Patzl M, Mostl E. Determination of autoantibodies to thyroglobulin, thyroxine and triiodothyronine in canine serum. J Vet Med A Physiol Pathol Clin Med 2003;50:72-78. 
5. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
6. Kemppainen RJ, Birchfield JR. Measurement of total thyroxine concentration in serum from dogs and cats by use of various methods. Am J Vet Res 2006;67:259-265.
7. Singh AK, Jiang Y, White T, et al. Validation of nonradioactive chemiluminescent immunoassay methods for the analysis of thyroxine and cortisol in blood samples obtained from dogs, cats, and horses. J Vet Diagn Invest 1997;9:261-268. 
8. Horney BS, MacKenzie AL, Burton SA, et al. Evaluation of an automated, homogeneous enzyme immunoassay for serum thyroxine measurement in dog and cat serum. Vet Clin Pathol 1999;28:20-28. 
9. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
10. Pirola I, Formenti AM, Gandossi E, et al. Oral liquid L-thyroxine (L-T4) may be better absorbed compared to L-T4 tablets following bariatric surgery. Obes Surg 2013;23:1493-1496. 
11. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101. 
12. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.
13. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876. 
14. Forthyron LT4 product insert: http://www.forthyron.com/data/acms/docs/treatment/1_forthyron_pi_200_400_en.pdf

Hypercalcemia in Canine Hypothyroidism

Hypercalcemia in a Dog with Primary Hypothyroidism

R. G. Lobettia

Journal of the South African Veterinary Association 2011;82: 242–243

Hypercalcemia is a relatively common problem in dogs, with the most common cause being malignancy-associated hypercalcemia (i.e., resulting from lymphoma, anal gland adenocarcinoma, multiple myeloma, or various other carcinomas). Other common causes include primary hyperparathyroidism, hypoadrenocorticism (Addison’s disease) chronic renal failure, and vitamin D toxicosis (1-3).

Hypothyroidism is not generally considered in the differential diagnosis or hypercalcemia in dogs. However, hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5), and, if left untreated, these hypothyroid dogs may continue to show slightly high serum calcium concentrations during adulthood (4).

In this case report (6), Lobetti describes a middle-aged dog with primary hypothyroidism that also developed symptomatic hypercalcemia. After instituting thyroid replacement therapy, both the hypercalcemia and associated clinical signs of polyuria resolved. This is the first report of this association between adult-onset hypothyroidism and symptomatic hypercalcemia in dogs.

Case Report
A 7-year old female beagle was examined because of polyuria and polydipsia, poor appetite, and weight gain. Physical examination revealed that the dog was slightly obese, with bradycardia (80 bpm). Routine blood work revealed marked hypercalcemia (3.27 mmol/L [13.1 mg/dl]; reference range, 2–3 mmol/L). A tentative diagnosis of hypothyroidism was made on the basis of a low serum T4 concentration (<6 nmol/L; reference range, 18–45 nmol/l) together with a high serum TSH value (1.05 ng/ml; reference range, 0.02–0.8 ng/ml).  

The dog was referred for further workup. On repeat serum biochemistry analysis, abnormalities included hypercholesterolemia (13.5 mmol/L [521 mg/dl]; reference range, 3–6 mmol/L) and hypercalcemia (3.44 mmol/ L [13.8 mg/dl]). Results of a complete blood count and urinalysis revealed no abnormalities.

An abdominal ultrasound examination, survey thoracic radiographs, and fine needle aspirate cytology of the spleen, liver and peripheral lymph nodes were all normal. Therefore, hypercalcemia of malignancy was considered unlikely.

A plasma parathyroid hormone (PTH) was low (7 pg/ml; reference range, 15–25 pg/ml). In addition, ultrasonography of the parathyroid glands was normal, making primary hyperparathyroidism unlikely.

The dog was treated with L-thyroxine (300 μg, twice a day). On follow up assessment 2 weeks later, the dog was more active and the bradycardia had resolved, but the polyuria and polydipsia were still present. A repeat serum calcium concentration remained high at 3.46 mmol/L (13.8 mg/dl). Supplementation with L-T4 was continued at 300 μg twice a day.

On recheck 9 weeks later, the dog was active and had lost weight, but now the polyuria and polydipsia had resolved. The serum concentrations of both calcium (2.97 mmol/ L [11.88 mg/dl]), and total T4 (25.5 nmol/L) has normalized.

Fifteen months after the initial diagnosis, the dog’s body weight was stable and her activity normal; no polyuria and polydipsia were reported. Serum concentrations of calcium (2.93 mmol/L [11.7 mg/dl]), T4 (32 nmol/L), TSH (0.11 ng/ml), and PTH (20 pg/ml) were all within the respective reference ranges.

Bottom Line
Little is known about the effects of hypothyroidism on calcium metabolism in adult dogs (1-3), but the effects appear to be mild and clinically insignificant. In agreement with that, humans with adult-onset hypothyroidism serum concentrations of calcium and phosphorus are typically within normal limits (7-9). However, up to 25% of children with congenital hypothyroidism can exhibit mild degrees of hypercalcemia (10), and mild hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5). The proposed mechanism for the hypercalcemia in hypothyroidism is decreased renal clearance and/or increased gastrointestinal absorption of calcium (11).

In the closing paragraph of this paper, Dr. Lobettia concludes that “the only logical explanation for the cause of the hypercalcemia in this dog would be hypothyroidism, as no other etiology was discovered, the hypercalcemia resolved with thyroxine therapy, and the PTH normalized.”

Unfortunately, another cause for this dog’s hypercalcemia must be considered — spurious total hypercalcemia, rather than true ionized hypercalcemia (12-14). In this dog, only the total calcium concentrations were measured, despite the well-documented fact that it is the ionized calcium fraction that has biologic activity.

Why ionized calcium was never measured in this dog is unclear, but it is possible that the serum ionized calcium value would have been normal, and the dog’s signs of polyuria may not have been caused by hypercalcemia after all.

In one study, it was documented that measuring total calcium concentrations tended to overestimate the perceived calcium value in dogs that were truly normocalcemic based on ionized calcium measurements. (13)  Use of total calcium or adjusted total calcium concentrations to predict the ionized calcium status in dogs could cause serious mistakes in diagnosis and case management, and that may have been the situation in the dog of this case report.

So before we add another differential to the differential list for hypercalcemia in dogs, just remember — always measure an ionized calcium to confirm true hypercalcemia (12-14)!

References:

1. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). Journal of Veterinary Internal Medicine 2009;23:514-519.
2. Feldman EC. Disorders of the parathyroid glands. In Ettinger S J, Feldman E C (eds), Textbook of Veterinary Internal Medicine (7th ed). Saunders Elsevier, St Louis. 2010;1722–1750.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT,Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Greco D S, Peterson M E, Cho D Y, et al. Juvenile-onset hypothyroidism in a dog. Journal of the American Medical Veterinary Association 1985;187: 948–950. 
5. Greco D S, Feldman E C, Peterson M E, et al. Congenital hypothyroid dwarfism in a family of giant schnauzers. Journal of Veterinary Internal Medicine 1991;5: 57–65.
6. Lobetti RG. Hypercalcaemia in a dog with primary hypothyroidism. Journal of the South African Veterinary Association 2011;82:242-243. 
7. Auwerx J, Bouillon R. Mineral and bone metabolism in thyroid disease: a review. Quarterly Journal of Medicine 1986;60: 737–752. 
8. Begic-Karup S, Wagner B, Raber W, et al. Serum calcium in thyroid disease. Wiener Klinische Wochenschrift 2001; 113: 65–68. 
9. Shivaleela MB, Poornima RT, Jayaprakash Murthy DS. Serum calcium and phosphorous levels in thyroid dysfunction. Indian Journal of Fundamental and Applied Life Sciences 2012;2:179 -183.
10. Verrotti A, Greco R, Altobelli E, et al. Bone metabolism in children with congenital hypothyroidism – a longitudinal study. Journal of Pediatric Endocrinology and Metabolism 1998;11: 699–705. 
11. Pérez A V, Picotto G, Carpentieri A R et al. Mini-review on regulation of intestinal calcium absorption. Emphasis on molecular mechanisms of transcellular pathway. Digestion 2008;77: 22–34. 
12. Schenck PA. Calcium homeostasis in thyroid disease in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 2007;37:693–708. 
13. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research 2005;66:1330-1336.
14. Schenck PA, Chew DJ. Calcium: total or ionized? Veterinary Clinics of North America: Small Animal Practice 2008;38:497-502.

Managing Hypothyroid Dogs with Low T4 Values Despite High Dose L-T4 Replacement

My "problem" patient is an 8-year-old, male hypothyroid Golden Retriever dog (37 kg) that isn't responding as expected to L-T4 supplementation.

The dog was diagnosed as hypothyroid about 3 years ago, based on the findings of low serum concentrations of both T4 and free T4 and a high serum TSH value. He responded well to initial L-T4 replacement therapy (0.5 mg BID) with complete resolution of all clinical signs of hypothyroidism.

We normally monitor and adjust the L-T4 dosage in our hypothyroid dogs by measuring a post-pill T4 value 4 to 6 hours after the morning dose of L-T4 is administered. The last normal post-pill serum T4 value in this dog was now over a year ago. Since that time, all of the serum T4 values have been  low to undetectable, despite a gradual doubling in the dog's L-T4 dose (now on 1.0 mg, BID). We've also sequentially changed our L-T4 preparation from a generic preparation to 3 different brand-name products (i.e., Thyro-tabs, Soloxine, and now Leventa), all to no avail.

The dog is not on any iodine supplements, and is fed a good brand of commercial dry dog food and a few milk bones daily. He has some chronic allergic skin issues (including ears) and has been treated in the past with steroids or antihistamines, but he has not been on any drugs for months.

Clinically, the dog appears happy and healthy and there is no indication of any other systemic disease. Despite the persistently low serum T4 values, the dog is not acting hypothyroid.

What else should I do to help get this dog's thyroid regulated? Can I go higher with his daily L-T4 dosage?

My Response:

There are a number of possible reasons why a hypothyroid dog could have persistently low serum T4 concentrations despite L-T4 supplementation.

Unreliable L-T4 preparation
Although most of the generic L-T4 preparations appear to work reasonably well most of the time, we do occasionally see treatment failures with these generics. In such cases, changing to a brand-name product easily solves the problem. In this dog, you have already ruled out this possibility by trying 3 major name-brand L-T4 products!

Poor bioavailability (poor absorption)
Again, the bioavailabilty (absorption) of brand-name L-T4 products is generally better than the generics, and this is one of the reasons name-brand products are more reliable.

In general, dogs will absorb the L-T4 best if given on an empty stomach. So if an owner has been administering the L-T4 with food, a change of dosing time to when the dog is fasted may help.  However, L-T4 is still absorbed reasonably well when given with food, so this would not explain why this dog has undetectable post-pill T4 values.

Compliance problems
In some cases, an owner may not be giving the L-T4 as directed. I've had owners think that they should not administer the medication on the morning when a recheck exam is scheduled.  We should always confirm that the L-T4 supplementation was administered on the morning of post-pill testing. If the medication wasn't given, a low T4 value should not be unexpected.

Incorrect dosage or underdosage
Obviously, we should always confirm that the dog's dose and L-T4 strength is correct.

Moderate to severe nonthyroidal illness 
In dogs with nonthyroidal illnesses, the serum thyroid hormone values are commonly suppressed, many times into the hypothyroid range (1-4). If a dog has a serious illness, it is possible that the post-pill T4 concentration would remain lower than anticipated. However, we do not generally see illness result in persistently low T4 concentrations, especially on high-dose L-T4 supplementation.

Drugs that suppress serum T4 concentrations
There are a number of drugs that can "falsely" suppress serum T4 (and sometimes free T4) values in dogs. The drugs most commonly associated with low T4 concentrations include the following:

• Phenobarbital (5-9)
• Trimethoprim-sulonamides (5, 10,11)
• Zonisamide (12)
• Clomipramine (Clomicalm) (13)
• Aspirin (5,14,15)
• Glucocorticoids (including topicals on eyes, ears or skin) (16,17)

If a dog is being treated with any of these drugs, it is certainly possible that the post-pill T4 concentration would be lower than anticipated. However, we do not generally see persistently low to undetectable post-pill T4 values, especially in dogs on high-dose L-T4 supplementation.

Laboratory error
Recently, both Antech and IDEXX Laboratories changed their method of T4 analysis from the "gold standard" RIA or chemiluminescence (Immulite) techniques to an automated enzyme immunoassay technique. While most of the T4 results measured by the gold standard methods (RIA or chemiluminescence) versus the new automated immunoassay method show very good agreement, the T4 values are discordant in about 5% of cases.

This problem occurs most commonly in dogs receiving thyroid supplementation. Characteristically, the T4 can be low to undetectable when measured by the automated immunoassay method but the post-pill T4 is normal or even high when measured by RIA or chemiluminescence. The reason for this discrepancy is T4 values between assay techniques is not clear.

In this dog, this could certainly be the problem. How is the lab measuring the T4? If done by automated immunoassay, I'd measure the next post-pill T4 value by either RIA or chemiluminescence to rule out this issue.

Bottom Line—When Is Post-Pill Monitoring Indicated?

From the clinical history, I was stuck by the fact that this dog —despite having persistently low T4 values on a very high dose of L-T4 supplementation— appears happy, healthy, and is not acting hypothyroid.  So my question is: should we even be monitoring post-pill T4 values in hypothyroid dogs which show complete resolution of all signs of disease after L-T4 treatment?

I use post-pill testing when a dog with confirmed hypothyroidism is not improving as well as expected to rule out issues with bioavailabilty, compliance, and unreliable L-T4 products (see my list above). I also use post-pill testing when I suspect iatrogenic hyperthyroidism, and I need to rule out L-T4 overdosage (18).

But if a dog has responded clinically to L-T4 as if this was a miracle drug, why even bother measuring the post-pill value? Why rock the boat and make dose adjustments when the owner and dog are happy? And if you do T4 monitoring in this situation, please don't get too excited if the post-pill T4 is slightly lower than anticipated. Remember that T4 doesn't act in the serum; it gets taken up by cells where it is converted to T3 and does all of its actions at an intracellular level. So it is very likely that thyroid hormone is still working fine in the tissues, even when measured values are not "high enough" in serum.

What are we treating here—the dog or the abnormal lab result?  At least for me, I treat my patient, not the post-pill T4 result. So when you recheck these patients, remember to take an overall look at the whole picture. That is, does the dog still look hypothyroid or are the clinical signs resolving? Has the mild anemia, hypercholesterolemia, or hypertriglyceridemia — all characteristic of this disease— persisted or have these abnormalities resolved on the L-T4 replacement therapy?  Is the owner happy or still not satisfied?

Again, if the dog has shown an excellent response to the current dose of L-T4, what do we really have to gain by monitoring a serum T4 concentration? In most cases, I'd say not as much as we might think.

References:

1. Peterson ME, Ferguson DC: Thyroid diseases, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Third Edition). Philadelphia, WB Saunders Co. 1989;1632-1675.
2. Peterson ME, Ferguson DC, Kintzer PP, et al. Effects of spontaneous hyper­adrenocorticism on serum thyroid hormone concentrations in the dog. American Journal of Veterinary Research 1984;45:2034-2038.  
3. Ferguson DC, Peterson ME. Serum free and total iodothyronine concentrations in dogs with spontaneous hyperadrenocorticism. American Journal of Veterinary Research 1992;53: 1636-1640. 
4. Kantrowitz LB, Peterson ME, Melián C, et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in dogs with nonthyroidal disease. Journal of the American Veterinary Medical Association 2001;219:765-769.  
5. Daminet S, Ferguson DC. Influence of drugs on thyroid function in dogs. Journal of Veterinary Internal Medicine 2003;17:463-472.  
6. Gaskill CL, Burton SA, Gelens HC, et al. Effects of phenobarbital treatment on serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs. Journal of the American Veterinary Medical Association 1999;215:489-496.  
7. Kantrowitz LB, Peterson ME, Trepanier LA, et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in epileptic dogs treated with anticonvulsants. Journal of the American Veterinary Medical Association 1999;214:1804-1808. 
8. Müller PB, Wolfsheimer KJ, Taboada J, et al. Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. Journal of Veterinary Internal Medicine 2000; 14:157-164.
9. Gieger TL, Hosgood G, Taboada J, et al. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. Journal of Veterinary Internal Medicine 2000;14:277-281. 
10. Williamson NL, Frank LA, Hnilica KA. Effects of short-term trimethoprim-sulfamethoxazole administration on thyroid function in dogs. Journal of the American Veterinary Medical Association 2002;221:802-806.  
11. Frank LA, Hnilica KA, May ER, et al. Effects of sulfamethoxazole-trimethoprim on thyroid function in dogs. American Journal of Veterinary Research 2005;66:256-259. 
12. Boothe DM, Perkins J. Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs. Journal of Veterinary Pharmacology and Therapeutics 2008;31:544-553. 
13. Gulikers KP, Panciera DL. Evaluation of the effects of clomipramine on canine thyroid function tests. Journal of Veterinary Internal Medicine 2003;17:44-49. 
14. Daminet S, Croubels S, Duchateau L,  et al. Influence of acetylsalicylic acid and ketoprofen on canine thyroid function tests. Veterinary Journal 2003;166:224-232.   
15. Panciera DL, Refsal KR, Sennello KA, et al. Effects of deracoxib and aspirin on serum concentrations of thyroxine, 3, 5, 3’-triiodothyronine, free thyroxine, and thyroid-stimulating hormone in healthy dogs. American Journal of Veterinary Research 2006; 67:599-603.
16. Torres SM, McKeever PJ, Johnston SD. Effect of oral administration of prednisolone on thyroid function in dogs. American Journal of Veterinary Research 1991; 52:416-421.  
17. Gottschalk J, Einspanier A, Ungemach FR, et al. Influence of topical dexamethasone applications on insulin, glucose, thyroid hormone and cortisol levels in dogs. Research in Veterinary Science 2011;90:491-497. 
18. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. Journal of Small Animal Practice 2002;43:334-340. 

Canine Hyperthyroidism and the Heart

Cardiovascular Manifestations of Iatrogenic Hyperthyroidism
in Two Dogs

by D.M. Fine, A. H. Tobias, and J.D. Bonagura

Journal of Veterinary 2010; 12: 141-146.

Background
While hypothyroidism is a common endocrine disorder in dogs, canine hyperthyroidism is rare. Like hyperthyroid cats, most dogs with naturally occurring hyperthyroidism have a functional thyroid tumor (1-3). However, unlike the situation in hyperthyroid cats, where most thyroid tumors are benign, almost all of these hyperthyroid dogs will have thyroid carcinoma. Therefore, the prognosis is generally guarded to poor.

The most common cause of hyperthyroidism in dogs is iatrogenic hyperthyroidism, which results from excessive intake of exogenous thyroid hormones. This is most commonly caused by the chronic administration of too-high a dose of L-thyroxine (L-T4) for treatment of hypothyroidism (1,3-5), but dietary hyperthyroidism secondary to consumption of meat contaminated with thyroid tissue may also rarely occur (6).

In general, most veterinarians consider thyroid hormone replacement to be a very safe and benign treatment. Iatrogenic hyperthyroidism, when it develops, is generally thought to have minimal undue effects. However, some dogs, especially those with underlying cardiac disease, are sensitive to even moderate L-T4 overdosage and will develop clinical complications of thyrotoxicosis (4).

This report by Fine et al (7) illustrates how chronic iatrogenic hyperthyroidism can lead to severe and life-threatening cardiovascular complications (e.g., tachycardia, arrhythmia, syncope) in dogs.

Case reports
Two dogs were diagnosed with iatrogenic thyrotoxicosis as a result of L-T4 overdosage. Both showed clinical signs of agitation, tachypnea, panting, and tachycardia.

One of the dogs (9-year-old, male Golden Retriever) also showed evidence of hyperthermia, polyuria, polydipsia, and polyphagia. The other dog (6-year-old, male castrated Great Pyrenees) also showed signs of severe weakness, syncope, and collapse.

Both dogs had been previously diagnosed with hypothyroidism and had been treated chronically with high doses of L-T4 (i.e., 40 μg/kg, BID, and 25 μg/kg, BID, respectively). On post-pill serum T4 testing, both dogs were confirmed as having severe hyperthyroidism.

Sinus tachycardia with supraventricular ectopy was diagnosed in one dog, whereas and syncope and atrial flutter was diagnosed in the other. Clinical signs and cardiac rhythm abnormalities resolved in both dogs with resolution of the thyrotoxicosis.

Conclusions of report
In both dogs of this report, iatrogenic hyperthyroidism resulted in clinical features and cardiovascular conduction disturbances of sinus tachycardia, supraventricular tachycardia, atrial fibrillation, and atrial flutter. Both dogs also had concurrent cardiac disease (degenerative atrioventricular valve disease) that might have contributed to the severity of their clinical signs. However, clinical signs and rhythm abnormalities resolved in both dogs with resolution of the thyrotoxicosis.

These cases illustrate that thyroid hormone supplementation is not always benign and that appropriate diagnostic studies, proper dosing, and regular post-treatment monitoring are essential to prevent adverse cardiovascular effects. Based on the 2 cases that we report here, this seems especially true for dogs with preexisting cardiac disease.

My Bottom Line:

Over the years, numerous therapeutic strategies have been recommended for the treatment of hypothyroid dogs. Today there is almost general agreement among endocrinologists that a dose of approximately 20–22 μg/kg once daily suffices in most cases, at least for long-term maintenance treatment (7,8).

The clinical response of hypothyroid dogs to once-daily therapy with this dosage is usually excellent. Although the use of divided BID dosing certainly results in less fluctuation of circulating T4 concentrations compared to once-daily administration, the biological action of thyroid hormones far exceeds that of their serum half-life. This presumably explains the clinical success of once-daily therapy. This once-daily dosage approach is also safer, since the total daily dosage administered is almost always less than when BID administration is used (8,9).

Both dogs of this report (7) had been treated chronically for years with high doses of L-T4, administered twice daily, which were at 2-to 4-fold higher than this recommended dose range of approximately 20 μg/kg/day (8,9).

While most dogs are relatively resistant to the thyrotoxic effects of excessive T4 supplementation, some dogs are sensitive to even moderate L-T4 over-dosage (4). If iatrogenic hyperthyroidism does develop in dogs undergoing treatment for hypothyroidism, the most common clinical signs include marked polydipsia and polyuria, followed by polyphagia, panting, weight loss, hyperactivity, tachycardia and pyrexia (1-5).

If any signs suggestive of hyperthyroidism develop in dogs on L-T4 replacement, a post-pill T4 concentration should be measured to document thyrotoxicosis, and the daily L-T4 dose should be decreased as needed. If present, all clinical signs of hyperthyroidism should resolve within a few days after the daily L-T4 dosage has been lowered.

References:

1. Peterson ME, Ferguson DC: Thyroid diseases, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, Third Edition. Philadelphia, WB Saunders Co., 1989;1632-1675.
2. Peterson ME: Hyperthyroidism and thyroid tumor in dogs. In: Melian C, Perez Alenza MD, Peterson ME, Diaz M, Kooistra H (eds): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008;113-125.
3. Mooney CT. Canine hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology, Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:86-91.
4. Refsal K, Nachreiner R. Monitoring thyroid hormone replacement therapy. In: Bonagura JD, Ed. Kirk’s Current Veterinary Therapy XII. Philadelphia: WB Saunders Co. 1995:364-368.
5. Mooney CT, Shiel RE. Canine hypothyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology, Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:63-85.
6. Köhler B, C. Stengel C, Neiger R. Dietary hyperthyroidism in dogs. Journal of Small Animal Practice 2012; 53, 182–184.
7. Fine DM, Tobias AH, Bonagura JD. Cardiovascular manifestations of iatrogenic hyperthyroidism in two dogs. Journal of Veterinary Cardiology 201012:141-146. 
8. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. Journal of Small Animal Practice 2002; 43, 334–340. 
9. Le Traon G, Brennan SF, Burgaud S, et al. Clinical evaluation of a novel liquid formulation of L-thyroxine for once daily treatment of dogs with hypothyroidism. Journal of Veterinary Internal Medicine 2009;23:43-49. 

Alternative Dosage Forms of L-Thyroxine for Hypothyroid Dogs

One of my patients is a large-breed dog suffering with hypothyroidism. Unfortunately, the owner can not administer the L-thyroxine tablets to the dog. The dog is able to expel everything the owners forces in its mouth, and he is too smart to take the pills when hidden in food or given in a pill pocket.

Are there any injectable L-T4 preparations that are available? If it is available, what brand is best? Would transdermal application of L-T4 work?

My Response:

First of all, can they put the L-T4 tablet into a pill pocket?  It's hard to believe that the dog will not eat the tablet if put into a meatball or piece of cheese!

If not, Merke Animal Health makes a liquid L-T4 product called Levanta solution that may be useful in this dog (1). Studies of the pharmacokinetics of this L-T4 preparation indicate that once daily administration is adequate (2). If the owners can't put the liquid directly into the dog' mouth, they could try adding the dose to his food.

If the dog doesn't accept the Levanta, a compounding pharmacy could prepare a flavored suspension of oral L-thyroxine.  For example, one on-line pharmacy offers a levothyroxine oral oil suspension in a wide variety of flavors, including: anchovy; apple; bacon; banana; beef; beef/chicken; chicken-marshmallow; double bacon; double beef; double chicken; double fish; duck; half bacon; lime; molasses; orange; peppermint; spearmint; strawberry; strawberry/marshmallow; tangerine; triple chicken; triple-fish; tutti fruitti; vanilla/marshmallow and venison. From this list, there should be something that will taste good to your dog.

An injectable form of L-T4 is indeed produced, available as a single-use vial containing either 100 μg or 500 μg of Levothyroxine sodium for injection (3). However, this product is intended as an emergency treatment for myxedema coma, not for long-term use (4). This preparation would be rather expensive, and it would likely be cost-prohibitive. So I wouldn't recommend it for long-term L-T4 replacement of this dog.

Unfortunately, transdermal application of L-T4 just doesn't work well at all to normalize serum T4 values. Results of two studies found that the hormone is not absorbed into the systemic circulation to have an effect on all tissues of the body (5,6). In support of that, of the few dogs that I have evaluated on transdermal L-T4, none have responded to the transdermal replacement therapy with a rise in serum T4 concentrations.

References:

1. Leventa (levothyroxine sodium) oral solution. Intervet/Schering-Plough Animal Health. Package insert available at: http://www.leventa.com/default.asp
2. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101.  
3. Levothyroxine Sodium for Injection. APP Pharmaceuticals . Package insert available at: http://editor.apppharma.com/PIs/Levothyroxine_for_Inj_45804C_Jan_08.pdf
4. Pullen WH, Hess RS. Hypothyroid dogs treated with intravenous levothyroxine. J Vet Intern Med 2006;20:32-37. 
5. Padula C, Pappani A, Santi P. In vitro permeation of levothyroxine across the skin. Int J Pharm 2008 12;349:161-165.
6. Padula C, Nicoli S, Santi P. Innovative formulations for the delivery of levothyroxine to the skin. Int J Pharm 2009;372:12-16.

Q & A: Allergic Reactions to L-Thyroxine in Dogs

My patient is a 2-year old, male castrated, Manchester Terrier that was recently diagnosed as hypothyroid. I placed him on levothyroxine (Thyro-tabs) at the dose of 0.3 mg, BID (the dog weighs 30 lb). 

The owners report that he is acting much better and has more energy on the thyroxine replacement.

The problem now is that the dog appears to have developed an allergy to the medication. He has many localized, pin-point bumps with crusts over the neck region and behind the elbows. In addition, it appears that the L-T4 has been making the dog vomit. 

I know that GI side-effects are rare, so we did a trial off the LT4 and the vomiting stopped. I then put the dog back on the L-T4, and the vomiting started again the same day!

Why would L-T4 cause these cutaneous and GI side effects? Should I try a different brand of thyroid hormone or switch to L-T3?

My Response:

Dogs can develop a drug allergy to thyroid hormone medication. Such allergic side effects are extremely rare but may include facial swelling, cutaneous eruptions and rash, and/or vomiting.

These drug allergies are likely not due to the L-T4 itself. Rather, the reactions appear to be an allergy to the color dye or filler contained within the L-T4 medication. Because the various brands and milligram sizes of L-T4 will differ in the color dye used in the tablets, the dog will need a different strength or brand to avoid the allergy.

References:

1. Magner J, Gerber P. Urticaria due to blue dye in synthroid tablets. Thyroid 1994;4:341. 
2. Granholt A, Thune PO. Urticaria and angioedema induced by antiphlogistics, preservatives and dye additives in food and tablets. Tidsskrift for den Norske Laegeforen. 1975;95:20-22.